This application is a continuation-in-part of Ser. No. 911,688 filed Sept. 25, 1986, U.S. Pat. No. 4,744,990.
This invention relates to the field of animal nutrition. In particular, the invention concerns nutritive supplements for warm-blooded animals.
It is well known that animals require proteins for their growth and health. Proteins are used to replace tissues, generate hormones, to provide the structural framework of the body (e.g. muscles, tendons, cartilage, etc..) and can also be consumed for energy.
Amino acids are the building blocks of proteins. In all living organisms, proteins and their constituent amino acids are continuously metabolized and exist in a dynamic equilibrium in the cells. Approximately 20 amino acids are common constituents of animal proteins. However, eight to ten of these amino acids are essential for the animal's survival. Since the animal's reserves of these essential amino acids are normally depleted within a few hours, the animmal must replenish its supply by ingesting proteins containing appropriate amounts of essential amino acids. The nutritional value of proteins used in aminal feed is therefore a function of the presence of these essential amino acids in proper amounts. However, feeds containing proteins of low nutritional value, i.e. deficient in one or more essential amino acids, can be supplemented with those amino acids or with other proteins containing the needed amino acids in order to attain the proper balance and enhance the nutrient usability of the proteins. Thus, plant proteins such as wheat, corn, and soybeans are commonly fortified with L-lysine, DL-methionine and/or other essential amino acids to upgrade the nutritional value of these common animal feeds.
It has been shown that the .alpha.-keto acid analogues of most of the essential amino acids can substitute for the corresponding amino acid in the diets of rats and men; see J. L. Wood and S. L. Cooley, Proc. Soc. Exp. Biol. Med. 85, 409-411 (1954), and J. H. Close, N. Engl. J. Med., 290: 663-667 (1974). In 1973 Dr. MacKenzie Walser of Johns Hopkins University proposed using .alpha.-keto acid analogues as non-nitrogen supplements to protein-reduced diets for kidney disease patients, who have difficulty eliminating nitrogen wastes. In the subsequent research, it was observed that the use of the keto analogues of the branched-chain essential amino acids leucine, isoleucine, and valine has a "protein-sparing" effect, i.e. use of these compounds prevented the body from using up amino acids in existing protein, thereby avoiding weight loss. The existing knowledge on the use of branched-chain .alpha.-keto acid analogues in humans was reviewed by Walser in J. Parenteral and Enteral Nutrition, 8(1), 37-41 (1983).
______________________________________ AMINO ACID .alpha.-KETO ACID ANALOGUE ______________________________________ ##STR1## ##STR2## Example: R = (CH.sub.3).sub.2 CH (isopropyl group) ##STR3## ##STR4## valine .alpha.-keto-isovaleric acid ______________________________________
The work of Walser on the use of branched-chain keto acid analogues as a nutritional substitute in humans has recently been extended to the field of animal nutrition. Dr. Steven Nissan of Iowa State University has shown that the use of the keto analogue of leucine, .alpha.-keto-isocaproic acid (KIC), apparently has beneficial effects when used as a food supplement for livestock. Wallaces Farmer (June 14, 1986); Pro Farmer (May 24, 1986). Among the advantages claimed when KIC is substituted for most of the diet leucine are: (1) increased feed efficiency and growth, particularly in ruminants; (2) improved quality and production of milk; (3) reduced cholesterol, particularly in eggs and milk; (4) increased wool production in sheep; and (5) increased immunological response.
It should be noted that KIC has special properties which distinguish it from other branched-chain .alpha.-keto acid analogues. Although KIC is the metabolic precursor of leucine, the two compounds have different metabolic fates in animals. KIC is absorbed mostly in the gut and utilized mostly in the liver. Leucine is absorbed mostly in the stomach and is metabolized in muscle tissue. KIC is also involved in steroid and carbohydrate metabolism.
The use of .alpha.-keto acid analogues as animal feed supplements possesses certain disadvantages. For example, the essential amino acid L-lysine is used as a commodity feed supplement. However, the direct keto analogue of this amino acid is non-nutritional. Another problem is that KIC is degraded substantially by the rumen and thus has to be protected by coating or additives if used with ruminants.
In addition, the branched-chain .alpha.-keto acid analogues corresponding to the essential amino acids leucine, isoleucine, and valine are unstable liquids or low-melting solids with very unpleasant odors. The calcium or sodium salts of the branched-chain .alpha.-keto acid analogues are the forms most commonly used as nutritive supplements. Although these salts have been shown to have the beneficial nutritive properties discussed above, they have several drawbacks: (1) bad taste; (2) unpleasant odor; (3) limited stability; and (4) degradation in the rumen. For humans, the bad taste is particularly problematic since it is difficult to mask. Walser has overcome this problem in some of his patents by forming the L-lysine, L-ornithine, and/or L-histidine salts of the branched-chain .alpha.-keto acid analogues. However, these salts are much more costly than simple metal salts. The unpleasant odor of branched-chain keto acid analogue salts, especially when contacted with the skin or other moist environment, makes branched-chain .alpha.-keto acid analogues' use objectionable to those who handle and administer the supplements.
It is the object of this invention to provide nutritional supplements for animal feeds which do not have the foregoing disadvantages of branched-chain keto acid analogues. It is believed that the 5-alkylidene and 5-hydroxy-5-alkyl substituted hydantoin analogues of the essential amino acids can serve such a purpose.
5-Substituted hydantoins are common chemical intermediates in the manufacture of branched-chain keto acid analogues. See, e.g., U.S. Pat. No. 4,069,251. They have the same carbon structure as the branched-chain keto acid analogues. However, these hydantoins are very stable powders with little odor or taste. In addition, these precursors obviously have a lower cost than the keto acid final products. The low water solubility and stability of the hydantoins should also allow them to survive the rumen better than unprotected branched-chain keto acid analogues.
______________________________________ 5-SUBSTITUTED KETO ACID HYDANTOIN AMINO ACID ANALOGUE ANALOGUE ______________________________________ ##STR5## ##STR6## ##STR7## Example ##STR8## 5-isopropylidene-hydantoin ______________________________________
The present invention is directed to the use of 5-alkylidene and 5-hydroxy-5-alkyl-substituted hydantoins as nutritive supplements in animal feed. As far as is known to applicants, these classes of hydantoin analogues of essential amino acids have never previously been tested or used for such purpose. However, it should be noted that 5-(2-methylthioethyl)-hydantoin, the hydantoin analogue of the essential amino aicd DL-methionine, has been used as an animal feed supplement to improve feed efficiency. See U.S. Pat. No. 3,644,629. Thiohydantoins (i.e. a hydantoin-type structure containing a sulfur atom as part of the ring structure) have also been used as animal feed additives to regulate metabolism and increase the conversion ratio of nutrients, South African 68/7562.
The carbon structure of the hydantoins which are the subject of this invention is stabilized through cyclization with a urea moiety. Enzymes called hydantoinases exist in nature that cleave urea from hydantoin rings to yield .alpha.-keto acids and amino acids. See M. Guivarch et al, Bull Soc. Chim. Fr. 1980 (1-2, Pt.2) 91-95 (CA 92: 176474); H. Yamada et al, J. Ferment. Technol. 1978 56(5), 484-91 (CA 90: 36129); U.S. Pat. No. 4,016,037; Japanese Pat. No. 70 08,633 (CA 73: 65026); H. Hasall and D. M. Greensberg, J. Bacteriol. 81, 755-61 (1961) (CA 55: 20088); R. C. Valentine and R. S. Wolfe, Biochem. Biophys. Res. Common. 5(4), 305-308 (1961). Hydantoins are generally metabolized in the liver via pyrimidine pathways. Thus, dihydrophyramidinase extracted from calf liver has been shown to act as a hydantoinase; see U.S. Pat. No. 3,964,970.